Pleomorphic Adenoma Gene Like-2 (PLAGL2) was identified as a transactivator of surfactant protein C (SP-C). In an attempt to examine the effect of PLAGL2 expression on SP-C production in vivo, an inducible, a lung specific PLAGL2 transgenic mouse model was developed. Lungs from transgenic mice developed an accelerated form of centrilobular emphysema following doxycycline (Dox) induction of PLAGL2 expression in type II and bronchiolar epithelial cells. This phenotype occurred in multiple mouse founders with varying PLAGL2 gene copies, indicating little contribution from integration sites or transgene copy numbers. Airway inflammation involving macrophages, neutrophils, and CD8 lymphocytes that frequently accompanies the development of COPD in humans did not appear in this PLAGL2 transgenic mouse model. Female mice displayed a higher incidence of emphysema, suggesting that this mouse model of centrilobular emphysema might mimic recent data demonstrating an increased prevalence of chronic obstructive pulmonary disease (COPD) among women. The initial characterization of this mouse model demonstrated that both PLAGL2 and SP-C expression were upregulated in distal airway epithelial cells in the induced mouse lung. The hypothesis of this study is that PLAGL2, which may play a role in surfactant protein homeostasis, is capable of initiating centrilobular emphysema in humans. This hypothesis will be tested with the supply of patient samples from LTRC. PLAGL2 expression will be examined on immunohistochemistry (IHC) staining of tissue sections from patients with histologic evidence of emphysema, COPD with predominantly chronic bronchitis, or controls. Relative levels of PLAGL2 expression will be evaluated using real-time PCR analysis of transcripts isolated from samples collected within the emphysema lesion by laser capture microdissection (LCM) technique. Scoring results obtained from both traditional IHC staining and the quantitative RT-PCR analysis of cDNA array of emphysema will be assessed to determine the correlation of PLAGL2 expression with disease severity. Given that long term lung specific expression of PLAGL2 results in centrilobular emphysema in mice, and data suggesting that PLAGL2 may either directly induce apoptosis or cause cytotoxic changes from overproduction of misprocessed SP-C, the probability that PLAGL2 plays a role in emphysema in humans with COPD is substantial. (End of Abstract)
Project Narrative: Using an animal model, a molecular abnormality in lung cells has been found correlated with the outcome of airspace enlargement, known as emphysema. This research will use the LTRC collected human patient samples to establish the concept of this molecule as a novel mechanism of pathogenesis of emphysema in humans.
| Yang, Yih-Sheng; Yang, Meng-Chun W; Weissler, Jonathan C (2011) Pleiomorphic adenoma gene-like 2 expression is associated with the development of lung adenocarcinoma and emphysema. Lung Cancer 74:12-24 |
| Yang, Yih-Sheng; Yang, Meng-Chun W; Guo, Yuhong et al. (2009) PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity. Am J Physiol Lung Cell Mol Physiol 297:L455-66 |
